Studies suggest that brain phospholipids are altered in Alzheimer disease (AD) and Down syndrome (DS). In AD, these changes have been reported to involve plasmalogens, which are ether lipids containing a 1-O-alkenyl linkage in the sn-1 position and which are enriched in arachidonic acid at the sn-2 position. To better understand the function of plasmalogens in brain, rates of biosynthesis of brain plasmalogens in vivo were assessed by intravenously infusing [1,1-3H]- hexadecanol into awake rats. Specific activity due to tracer was followed in different brain plasmalogen pool and precursor compartments as a function of time after injection, using novel analytical techniques. Rates of influx and turnover were determined in terms of compartmental kinetics. In vivo plasmalogen biosynthesis is very dynamic; half-lives for ethanolamine- and choline plasmalogen are as short as 5.6 h and 1.7 h, respectively. These short half-lives and therefore high turnover rates were calculated to consume 6.9%-7.6% of energy in the form of ATP, consumed by the brain as a whole. Additionally, ethanolamine plasmalogen levels were found to be reduced by 37% in brains from older DS subjects compared with control brains. The changes do not appear to reflect AD neuropathology in DS, as they also were found in the cerebellum, where AD neuropathology is absent. In AD brain, the apolipoprotein E4 genotype was associated with reduced phospholipase A2 activity in frontal cortex and hippocampus, but not in cerebellum, consistent with dysfunction of phospholipid metabolism in pathologically affected but not unaffected brain regions in AD. - Alzheimer disease, Down syndrome, Phospholipase A2, Ether lipids, Phospholipids, Apolipoprotein E, Knockout mice